Project Summary/Abstract Significance: The failure of bone fractures to adequately repair in elderly patients causes significant morbidity and mortality each year in the United States. This problem will continue to be exacerbated by an aging population, with a 160% increase in hip fractures alone expected by 2040 and significant costs in lost work, quality of life, physical therapy, extended care facility stays, and surgeries. Conventional therapy includes mechanically stabilizing the fracture, but thus far, no systemic bone anabolic therapies exist to target and accelerate fracture repair. Preliminary Data: Novosteo Inc. has developed a fracture targeted therapeutic that has demonstrated a dramatic acceleration in healing time and callus formation and remarkable specificity to bone fracture sites. Administered systemically through subcutaneous injection, the drug selectively accumulates on hydroxyapatite, the inorganic portion of bone exposed in a fracture, providing a site-specific dose of anabolic agent. The targeted specificity to the fracture callus limits accumulation of the drug in off-target tissues, reducing the potential for side effects. Also, the systemic delivery route allows for multiple doses of anabolic agent to be administered rather than a single bolus possible via surgery. While bypassing the invasiveness of surgery, the drug mimics a locally- administered anabolic in that drug accumulation is limited to the fracture site and sufficient dose can be administered for accelerated healing. Thus far, Novosteo's biodistribution studies have demonstrated no detectable toxicities at doses that dramatically accelerate fracture repair. Proposal: The overall goal of this Fast-Track SBIR proposal will be to prepare the proposed fracture-targeted therapy for clinical trials. The first step will be to optimize the chemistry of Novosteo's lead candidate. This will be accomplished in Phase I by performing the following: (1) optimization of the fracture targeting ligand composition and (2) conducting a thorough analysis of the fracture targeted drug's toxicity. Phase II will focus on preparing the fracture targeted drug for IND. This will be accomplished by: (1) validating Phase I results in a non-rodent model, (2) conducting MTD, GLP pharmacokinetics, and GLP toxicity studies, and (3) conducting genotoxicity analysis to evaluate any morphogenic dangers. Conclusion: The ability to accelerate bone fracture repair is a fundamental need that has not been addressed by conventional methods. If granted, the completion of the proposed studies would enable the optimization and pre-clinical evaluation of an indispensable therapy for bone fracture repair. Its safety and efficacy could then be explored and evaluated in other settings where accelerated bone regeneration is desired, such as hairline vertebral fractures in osteoporosis patients or craniofacial reconstruction and repair.